This application is a resubmission of our pilot proposal aimed at testing the relationship between genotype, response to an alcohol challenge and treatment response. Evidence from our center suggests that a functional polymorphism of the mu-opioid receptor (OPRM1) may be associated with clinical response to the opioid antagonist, naltrexone (NTX) in the treatment of alcohol dependence. A similar finding has been reported from the NIAAA COMBINE study. The polymorphism is a single nucleotide polymorphism (SNP) in exon 1 (Asn40Asp). In retrospective analyses of patients adherent to NTX, persons with one or two copies of the Asp40 variant had a 73.9 % response (no relapse to alcohol use);whereas subjects homozygous for the Asn40 allele only had a 49.0 % positive response rate to treatment (p=0.040). While certainly not definitive, these data suggest the potential for a genetic difference between those who do and do not respond to NTX. We have proposed a pilot study combining a human laboratory exposure to alcohol and outpatient treatment response. Specifically, we will test the degree to which specific genetic markers alter the relationship between subjective and objective measures of response to alcohol ingestion among alcohol dependent adults in a laboratory environment. This alcohol response endophenotype will then be compared to treatment response over the next 12 weeks. To meet the aim of the pilot study, 40 alcohol dependent men will be recruited for participation. During a 2 day inpatient stay, subjects will administered two alcohol challenge sessions (one session after receiving a placebo and one session treatment with naltrexone). After completion of the challenge sessions, subjects will receive 12 weeks of outpatient treatment with naltrexone. During outpatient treatment, all patients will also receive Medical Management (MM) as designed for the NIAAA-funded, multi-site project (COMBINE), to support abstinence while providing pharmacotherapies in a safe, psycho-educational format. Results from this trial will assist in developing a pharmacogenetic trial of naltrexone which would form the basis for developing a biological marker for treatment matching.